19. 09. 2024
Postsynaptic machinery for local control of mTORC1 signaling and memory storage
Přednáší: Isabel Pérez Otaño (otevře se v novém okně) / Instituto de Neurociencia de Alicante (Spanish Research Council, Universidad Miguel Hernández de Elche)
Anotace: De novo protein synthesis mediates neural circuit rewiring and memory storage through specific and lasting modifications of subsets of synapses. Yet the extensive compartmentalization of neurons presents a major challenge to achieving a selective regulation at the synapse level. We now identify a signalosome complex that nucleates the activation of the mammalian target of rapamycin complex 1 (mTORC1) and mTORC1-dependent protein synthesis in response to synaptic activity. The complex is formed by the postsynaptic scaffold GIT1, the p21-activated protein kinase exchange factor beta (βPIX), the mTOR kinase and Raptor. Synaptic targeting of GIT1/βPIX/mTORC1 complexes requires intrinsic localization signals within GIT1 and the formation of macromolecular GIT1/βPIX condensates. Disrupting GIT1/βPIX condensates by expressing mutants unable to bind each other or unable to associate into large molecular oligomers reduces mTOR recruitment to synaptic spines. We further show that complex composition, localization and function are set by positive (Shank3) and negative (GluN3A-NMDA type glutamate receptors) regulators that tune the postsynaptic availability of translation machinery as a function of developmental stage, brain region and cell type. At the behavioral level, modulation of GIT1/mTORC1 signaling determines the postnatal emergence of memory consolidation mechanisms; in adult brains, the types of memories that are persistently stored and resilience to stress. Together, our findings reveal GIT1/βPIX condensates as essential platforms for targeting mTOR signaling to synapses, and suggest modulation as a promising target for intervention in neurodevelopmental, cognitive and emotional disturbances.
Multiplexed frequency filtering at individual presynaptic terminals
Přednáší: John F. Wesseling (otevře se v novém okně) / Instituto de Neurociencia de Alicante (Spanish Research Council, Universidad Miguel Hernández de Elche)
Anotace: Synapses are often modeled as straightforward information conduits between neurons, where memories are stored via mechanisms that are blind to frequency modulation within presynaptic spike trains. However, our studies of rate limiting steps in synaptic vesicle trafficking within presynaptic terminals have generated a new mathematical and cell biological framework where individual sites for neurotransmitter release function as independent band-pass frequency filters. If correct synaptic transmission might be better understood as multiplexed frequency filtering with extensive capacity to store information by tuning individual release sites in addition to modulating the overall number of release sites and postsynaptic mechanisms. For this seminar, I will explain the backstory and then summarize some of our recently published work where we tested the surprising prediction of the new framework that quickly and slowly mobilized reserve synaptic vesicles are processed in parallel.
